CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation

Burns, David M.; D’Ambrogio, Andrea; Nottrott, Stephanie; Richter, Joel D.

doi:10.1038/nature09908

Cited by 177 publications

(168 citation statements)

References 27 publications

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“…We then show that this degradation pathway is disrupted in most cancers, as well as in the noncancerous proliferative skin disease psoriasis. This provides evidence for a pathway in which PAPD5, a tumor suppressor previously shown to stabilize tumor protein p53 (TP53) mRNA (29), also regulates oncomiR degradation.…”

Section: Significancementioning

confidence: 70%

“…In liver cells, an additional biological function of PAPD5 was recently discovered in a regulatory pathway affecting the tumor suppressor TP53 (also known as p53) (29). In this pathway, PAPD4 stabilizes the miRNA miR-122 by 3′ adenylation (19), thereby stimulating translational repression by miR-122 of the cytoplasmic polyadenylation element-binding protein CPEB.…”

Section: Discussionmentioning

confidence: 99%

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PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

Boele

Persson

Shin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

135

143

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Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3′ end, and moreover that the 3′ end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3′-to-5′ direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.nucleotidyl transferase | microRNA processing

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Section: Significancementioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

Boele

Persson

Shin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

135

143

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“…143 Understanding the structural restrain of its structure is pivotal to understand the function of p53 [144][145][146] as well as its potential therapeutic exploitation. 147,148 The regulation of p53 protein half-life is crucial to his function 149,150 and, consequently, for cancer progression. [151][152][153] This proteosomal degradation is indeed a powerful therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants

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“…PAPD4 (GLD2) is an important regulator of late spermatogenesis and is the first example of a GLD-2 family member playing a significant role in male gametogenesis [31] . Translational regulation of p53 mRNA and cellular senescence is coordinated by GLD2/miR-122/CPEB/GLD4 [32] .…”

Section: Discussionmentioning

confidence: 99%

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

Laumonnier

Syrovets

et al. 2011

Acta Pharmacol Sin

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Aim: To identify proteins that interact with the C-terminal fragment of annexin A2 (A2IC), generated by plasmin cleavage of the plasmin receptor, a heterotetramer (AA2t) containing annexin A2. Methods: The gene that encodes the A2IC fragment was obtained from PCR-amplified cDNA isolated from human monocytes, and was ligated into the pBTM116 vector using a DNA ligation kit. The resultant plasmid (pBTM116-A2IC) was sequenced with an ABI PRISM 310 Genetic Analyzer. The expression of an A2IC bait protein fused with a LexA-DNA binding domain (BD) was determined using Western blot analysis. The identification of proteins that interact with A2IC and are encoded in a human monocyte cDNA library was performed using yeast two-hybrid screening. The DNA sequences of the relevant cDNAs were determined using an ABI PRISM BigDye terminator cycle sequencing ready reaction kit. Nucleotide sequence databases were searched for homologous sequences using BLAST search analysis (http://www.ncbi.nlm.nih.gov). Confirmation of the interaction between the protein LexA-A2IC and each of cathepsin S and SNX17 was conducted using a small-scale yeast transformation and X-gal assay. Results: The yeast transformed with plasmids encoding the bait proteins were screened with a human monocyte cDNA library by reconstituting full-length transcription factors containing the GAL4-active domain (GAL4-AD) as the prey in a yeast two-hybrid approach. After screening 1×10 7 clones, 23 independent β-Gal-positive clones were identified. Sequence analysis and a database search revealed that 15 of these positive clones matched eight different proteins (SNX17, ProCathepsin S, RPS2, ZBTB4, OGDH, CCDC32, PAPD4, and actin which was already known to interact with annexin A2). Conclusion: A2IC A2IC interacts with various proteins to form protein complexes, which may contribute to the molecular mechanism of monocyte activation induced by plasmin. The yeast two-hybrid system is an efficient approach for investigating protein interactions.Keywords: yeast yeast two-hybrid system; human monocyte; plasmin receptor; C-terminal fragment of annexin A2 (A2IC); protein-protein interaction Acta

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CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation

Cited by 177 publications

References 27 publications

PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

Molecular dynamics of the full-length p53 monomer

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

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